TY - JOUR
T1 - MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma
AU - Tao, Ling
AU - Mohammad, Mahmoud A.
AU - Milazzo, Giorgio
AU - Moreno-Smith, Myrthala
AU - Patel, Tajhal D.
AU - Zorman, Barry
AU - Badachhape, Andrew
AU - Hernandez, Blanca E.
AU - Wolf, Amber B.
AU - Zeng, Zihua
AU - Foster, Jennifer H.
AU - Aloisi, Sara
AU - Sumazin, Pavel
AU - Zu, Youli
AU - Hicks, John
AU - Ghaghada, Ketan B.
AU - Putluri, Nagireddy
AU - Perini, Giovanni
AU - Coarfa, Cristian
AU - Barbieri, Eveline
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/6/28
Y1 - 2022/6/28
N2 - Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. MYCN amplification is found in half of high-risk NB patients; however, no available therapies directly target MYCN. Using multi-dimensional metabolic profiling in MYCN expression systems and primary patient tumors, we comprehensively characterized the metabolic landscape driven by MYCN in NB. MYCN amplification leads to glycerolipid accumulation by promoting fatty acid (FA) uptake and biosynthesis. We found that cells expressing amplified MYCN depend highly on FA uptake for survival. Mechanistically, MYCN directly upregulates FA transport protein 2 (FATP2), encoded by SLC27A2. Genetic depletion of SLC27A2 impairs NB survival, and pharmacological SLC27A2 inhibition selectively suppresses tumor growth, prolongs animal survival, and exerts synergistic anti-tumor effects when combined with conventional chemotherapies in multiple preclinical NB models. This study identifies FA uptake as a critical metabolic dependency for MYCN-amplified tumors. Inhibiting FA uptake is an effective approach for improving current treatment regimens.
AB - Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. MYCN amplification is found in half of high-risk NB patients; however, no available therapies directly target MYCN. Using multi-dimensional metabolic profiling in MYCN expression systems and primary patient tumors, we comprehensively characterized the metabolic landscape driven by MYCN in NB. MYCN amplification leads to glycerolipid accumulation by promoting fatty acid (FA) uptake and biosynthesis. We found that cells expressing amplified MYCN depend highly on FA uptake for survival. Mechanistically, MYCN directly upregulates FA transport protein 2 (FATP2), encoded by SLC27A2. Genetic depletion of SLC27A2 impairs NB survival, and pharmacological SLC27A2 inhibition selectively suppresses tumor growth, prolongs animal survival, and exerts synergistic anti-tumor effects when combined with conventional chemotherapies in multiple preclinical NB models. This study identifies FA uptake as a critical metabolic dependency for MYCN-amplified tumors. Inhibiting FA uptake is an effective approach for improving current treatment regimens.
KW - Animals
KW - Cell Line, Tumor
KW - Fatty Acids
KW - N-Myc Proto-Oncogene Protein/genetics
KW - Neuroblastoma/metabolism
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UR - http://www.scopus.com/inward/citedby.url?scp=85132969222&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-31331-2
DO - 10.1038/s41467-022-31331-2
M3 - Article
C2 - 35764645
AN - SCOPUS:85132969222
SN - 2041-1723
VL - 13
SP - 3728
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3728
ER -